Several pieces of evidence suggest that endogenous opioids and zinc may interact to regulate neuronal excitability within the hippocampal formation. The purpose of this project is to conduct a systematic investigation into the effects of zinc on hippocampal neuronal excitability, with an emphasis on its interaction with enkephalin. The goal is to explain the nature of the effects of zinc and the mechanism(s) for its interaction with enkephalin. First it was necessary to determine the manner in which zinc levels were to be altered and the model for equating the significance of these changes to the functioning of the organism. As an initial approach we chose to attempt to alter zinc levels by systemic administration of zinc chloride or the intraviral zinc chelator, dithizone. The biological assay used was occurrence of wet dog shakes and seizures following subcutaneous administration of kainic acid (KA). We were unable to confirm the report of Porsche that subcutaneously administered Zn C1-2 prevents KA induced seizures in rats. Instead, we found no effect of Zn C1-2 in doses up to and including 100 mg/kg. This was true whether zinc was given before or after KA. In contrast, intraperitoneal injection of dithizone (12.5-100 mg/kg) has a profound and dose related effect on the toxicity of KA. When given 15 minutes after the subcutaneous injection of KA, it markedly potentiates KA toxicity. However, when KA is given 24 hours after dithizone, the toxicity of KA is reduced. It appears, then, that dithizone may prove to be extremely useful as a tool for exploring the actions of zinc on the hippocampus. Work in progress involves: 1) quantitation of changes in zinc levels in the hippocampus as a result of the various manipulations, examination of changes in hippocampal levels of enkephalin and dynorphin and examination of electrophysiological effects of dithizone in the hippocampus.